Genetic influences and their interaction with environmental factors are thought to be important determinants of asthma incidence, severity, and response to treatment. The importance of determining whether genetic determinants shape the response to regular use of inhaled beta-agonists has been increased by changes in the characteristics of beta-agonists, with a substantially longer duration of bronchodilator action and improved efficacy in control of asthma symptoms. Despite the availability of the inhaled beta-agonists for more than 30 years, limited information is available on the role of genetic polymorphisms and their associated responses to treatment. Recent findings of a genotyped stratified prospective trial conducted by the NIH Asthma Clinical Research Network (ACRN) prompted the organization of a meeting to examine the role of polymorphisms of the beta-adrenergic receptor gene in relation to asthma treatment as well as to consider new opportunities in the field of asthma pharmacogenetics. Accordingly, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group entitled "Polymorphisms of the Beta-adrenergic Receptor Gene: Implications for the Pharmacotherapy of Asthma" on June 17-18, 2003.
The working group proposed various scenarios that should be considered for developing future studies, ranging from studies that include 1,000 to 6,000 subjects sample sizes. However, challenges are not limited to the sample size but to phenotypic variations, pharmacological interactions, or gene-environment interactions, just to mention a few. Given the potential costs of such large studies, collaboration with the pharmaceutical industry or with other governmental agencies may be desirable in performing such studies. Despite major recent advances in the understanding of the structure and function of the beta2 adrenergic receptor (beta2AR), several questions with relevant clinical implications remain to be answered, requiring a stepwise approach. Some questions relate to the genotyped stratified prospective trial "BARGE" observations to the use of long-acting beta-agonists; the possible selective racial/ethnic predisposition to a beta2AR polymorphism or a related mechanism that increases risk for severe exacerbations; the influence of inhaled steroids on the reduction in pulmonary function that occurs within the Arg/Arg genotype with regular -agonists; the role of gene by dose relationship on therapeutic responses; the mechanism of the prolonged decline in pulmonary function in the Arg/Arg group that occurs even when regular beta-agonists are discontinued; the relationship between beta2AR polymorphisms and nocturnal asthma; and the possible functional importance of genetic variation in the 3' UTR and its influence on the bronchodilator phenotype. The workshop participants recognized that individual gene or individual variant within a gene is likely to confer only a small proportion of explained phenotypic variance, and that multiple variants in multiple genes in a pathway will be necessary to explain a significant percentage of variation in treatment response. Therefore, a combination of multiple single nucleotide polymorphisms or haplotypes across many genes will be needed to develop diagnostic tests that will be predictive for beta-agonist treatment response.
Working Group Members
- Homer Boushey, MD, Department of Medicine, University of California San Francisco
- Scott Weiss, MD, Channing Laboratory, Brigham and Women's Hospital
- Stephen Liggett, MD, Department of Medicine, University of Cincinnati
- Carole Ober, PhD, Department of Human Genetics, University of Chicago
- Fernando Martinez, MD, Arizona Respiratory Center, University of Arizona College of Medicine
- Elliot Israel, MD, Department of Medicine, Brigham and Women's Hospital
- Michael Wechsler, MD, Department of Medicine, Brigham and Women's Hospital
- Julie A. Johnson, Pharm.D., Department of Pharmacy Practice, University of Florida
- Robert Lemanske, MD, Department of Pediatrics, University of Wisconsin
- Stanley J. Szefler, MD, Department of Pharmacology, National Jewish Medical & Research Center
- William J. Calhoun, MD, Department of Medicine, University of Pittsburgh
- Vernon M. Chinchilli, PhD, Department of Health Evaluation Sciences, Pennsylvania State University